CN101622232A - 6-oxo-6, 7-dihydro-5H-dibenzo [B, D] aza-7-yl derivative - Google Patents
6-oxo-6, 7-dihydro-5H-dibenzo [B, D] aza-7-yl derivative Download PDFInfo
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- CN101622232A CN101622232A CN200880006496A CN200880006496A CN101622232A CN 101622232 A CN101622232 A CN 101622232A CN 200880006496 A CN200880006496 A CN 200880006496A CN 200880006496 A CN200880006496 A CN 200880006496A CN 101622232 A CN101622232 A CN 101622232A
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- fluoro
- dibenzo
- azepine
- dihydro
- oxo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to 6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl derivatives of Formula (I) wherein R <1>, R <2> and R< 3> are as defined herein, as gamma-secretase inhibitors useful in the treatment of Alzheimer's disease or common cancer including but not limited to cervical carcinomas and breast carcinomas and malignancies of the hematopoietic system.
Description
The present invention relates to the 6-oxo-6 of formula I, 7-dihydro-5H-dibenzo [b, d] azepine
-7-radical derivative with and suitable medicinal optically pure epimer or its mixture
Wherein
R
1Be hydrogen or the low alkyl group that replaced by halogen;
R
2It is low alkyl group;
R
3The low alkyl group that is replaced by halogen ,-(CH
2)
n-cycloalkyl or-(CH
2)
n-phenyl, wherein benzyl ring is unsubstituted or is replaced by halogen;
N is 0,1 or 2.
Term used herein " low alkyl group " expression contains the saturated straight chain or the branched-chain alkyl of 1 to 7 carbon atom, for example, and methyl, ethyl, propyl group, sec.-propyl, just-butyl, different-butyl, 2-butyl, tert-butyl etc.Preferred low alkyl group is the low alkyl group with 1-4 carbon atom.
Term " low alkyl group that is replaced by halogen " expression wherein at least one hydrogen atom by the displaced alkyl as defined above of halogen, for example CF
3, CHF
2, CH
2F, CH
2CF
3, CH
2CH
2F, CH
2CF
2CF
3, CH
2CF
2CH
3, CH
2CH
2CF
2CF
3, CH
2CH
2CF
3, CH
2CH
2CH
2CF
3Those low alkyl groups that replaced by halogen that compound exemplified of embodiment hereinafter.
Term " cycloalkyl " expression contains the aromatic carbocyclic of 3 to 6 carbon atoms, for example cyclopropyl, cyclopentyl or cyclohexyl.Preferred cycloalkyl is a cyclopropyl.
The compound that has been found that general formula I is gamma-secretase (secretase) inhibitor, and they can be used for treating alzheimer's disease or common cancer (including but not limited to cervical cancer and mammary cancer) and malignant tumor of hematopoiesis system.The advantage that is used in the formula I compound in the medicine is to compare with disclosed compound among the WO 2005/023772, and it has enhanced gamma-secretase restraining effect and good thermodynamic solubility.
Alzheimer's disease (AD) is the common cause of the dementia in stage in old age.The pathological characteristics of AD is the interior deposition of the amyloid brain of neurofibrillary tangles form in extracellular patch and the cell.Amyloid plaque mainly comprises 4 amyloid (Abeta peptide), and this peptide is generated by beta amyloid precursor protein (APP) by a series of proteolytic cleavage steps.Determined several forms of APP, wherein the abundantest is the albumen of 695,751 and 770 amino acid lengths.They are all produced by single-gene by differential splicing.The Abeta peptide is derived from the same area of APP, but N-is terminal different with C-, and primary categories has 40 and 42 amino acid lengths.
The Abeta peptide be by be called as β-and the serial action of 2 kinds of proteolytic ferments of gamma-secretase produce by APP.Beta-secretase at first carries out cracking in being located in the zone, APP extracellular of striding diaphragm area (TM) outside, produce the C-terminal fragment of the APP that contains TM-and kytoplasm (cytoplasmatic) zone (CTF β).CTF β is the substrate of gamma-secretase, and the several adjacent positions of gamma-secretase in TM carry out cracking, produces A β peptide and kytoplasm fragment.Most of Abeta peptides all have 40 amino acid lengths (A β 40), and the small portion kind is carried two other amino acid at its C-end.The latter is considered to pathogenic stronger 4 amyloid.
Beta-secretase is a kind of typical aspartyl protease.Gamma-secretase is a kind of proteolytic activity of being made up of several albumen, does not also understand its definite composition fully.But presenilin is this active important component and can represents one group of new atypical aspartyl protease that these atypical aspartyl proteases carry out cracking and itself are polytopic membranins in the TM of their substrate.Other important component of gamma-secretase may be the products of nicastrin and aph1 and pen-2 gene.The substrate of verified gamma-secretase is the albumen of APP and Notch receptor family, and still, gamma-secretase has loose substrate specificity, further the incoherent membranin of cracking and APP and Notch.
The generation absolute demand gamma-secretase activity of Abeta peptide.Use hereditary means (promptly removing the presenilin gene) and lower molecular weight to suppress compound and proved this point.Because according to the amyloid hypothesis of AD, the generation of Abeta and deposition are the basic reasons of described disease, thus think gamma-secretase optionally, effective inhibitors will can be used for prevention and treatment AD.
Therefore, the present invention will compound can be by the blocking-up gamma-secretase active and reduce or prevent that various amyloid source property (amyloidogenic) Abeta peptide from forming and be used for the treatment of AD.
Many document descriptions the have been arranged existing knowledge that suppresses about gamma-secretase, for example following publication:
Nature Reviews/Neuroscience, the 3rd volume, in April, 2002/281,
Biochemical Society Transactions (2002), the 30th volume the 4th part,
Current?Topics?in?Medicinal?Chemistry，2002，2，371-383，
Current Medicinal Chemistry, 2002, the 9 volumes, o. 11th, 1087-1106,
Drug?Development?Research，56，211-227，2002，
Drug Discovery Today, the 6th volume, the 9th phase, May calendar year 2001,459-462,
FEBS?Letters，483，(2000)，6-10，
Science, the 297th the volume, 353-356, in July, 2002 and
Journal of Medicinal Chemistry, the 44th volume, the 13rd phase, 2001,2039-2060.
Theme of the present invention have formula I compound itself, formula I compound or its suitable medicinal optically pure epimer or mixture preparation be used for the treatment of with gamma-secretase suppress in the medicament of diseases associated purposes, they preparation, based on the medicament of compound of the present invention and preparation thereof and formula I compound in control or prevent purposes in alzheimer's disease or the cancer.
Another theme of the present invention is optically pure epimer or its mixture of the form of ownership of formula I compound.
Preferred formula I compound is R wherein
1Be hydrogen and R
3Those compounds of the low alkyl group that is replaced by halogen, for example following compounds:
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide,
(R)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide,
(R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide,
(R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide or
(S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide.
Preferred formula I compound also has wherein R
1The low alkyl group and the R that are replaced by halogen
3Those compounds of the low alkyl group that is replaced by halogen, for example following compounds:
(R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, or
(S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide.
Formula I compound of the present invention with and pharmaceutically useful salt can prepare with method as known in the art, for example can prepare with method described below, this method comprises
A) with the compound of formula II
With the compound reaction of formula III,
Obtain the compound of formula I,
Substituting group wherein has above-mentioned implication, perhaps,
B) with the compound of formula IV
With formula NH
2R
3Amine reaction, obtain the compound of formula I,
Substituting group wherein has above-mentioned implication,
With,
If necessary, the mixture (R/S) with the epimerization form of formula I compound changes into epimer (R) and epimer (S).
Can find detailed description hereinafter with among the embodiment 1-14.The parent material of formula II compound is a known compound, and the amine of formula III can prepare as described in the schema 2.
Schema 1
The compound of formula II and the solution of compound in solvent such as tetrahydrofuran (THF) of formula III are at room temperature reacted with 1-hydroxyl-benzotriazole hydrate, diisopropyl ethyl amine and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night., handle except that desolvating by distillation, use the ethyl acetate/heptane wash-out, obtain the compound of formula I with silica gel chromatography.
Schema 2
R
4=low alkyl group
The preparation of formula III compound
In the propanedioic acid dialkyl group propyl diester of formula V and the suspension of cesium carbonate in dimethyl formamide, use the air bubbling.Under about 10-20 ℃, add entry, at room temperature continued stir about 3 hours.Remove dimethyl formamide then.Add entry, use extracted with diethyl ether, obtain the mono alkyl ester of formula VI.
Be dissolved in the mono alkyl ester of formula VI in the tetrahydrofuran (THF) and be cooled to 0 ℃.Add 1-hydroxyl-benzotriazole hydrate, diisopropyl ethyl amine and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride, at room temperature continued stir about 4 days.Add aqueous hydrochloric acid then.Behind extraction and purifying, obtain the compound of formula VII.
By handling (with Virahol/heptane 10/90 wash-out) in the enterprising circumstances in which people get things ready for a trip of Chiralpak AD spectrum in a usual manner the mixture separation of the epimerization form of the formula VII compound of acquisition is become epimer R and S.
The acid of formula III can be prepared as follows:
The solution of lithium hydroxide in water at room temperature stirred with the formula VII compound that is arranged in tetrahydrofuran (THF) (enantiomorph that back at first elutes) spend the night.At first water/extracted with diethyl ether is used aqueous hydrochloric acid/ethyl acetate extraction then, obtains the acid of required formula III.
The preparation of formula I compound
With 7-amino-5H of formula II, 7H-dibenzo [b, d] azepine
The solution of the compound of-6-ketone and formula VI in tetrahydrofuran (THF) is cooled to 0 ℃, adds 1-hydroxyl-benzotriazole hydrate, diisopropyl ethyl amine and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue at room temperature to stir to spend the night.Remove by distillation desolvate and carry out chromatography after, obtain the compound of formula VIII.
Then, the mixture that will be arranged in the formula VIII compound that is obtained of tetrahydrofuran (THF) and the lithium hydroxide that is in water at room temperature stirs and spends the night.Solvent evaporated, with residue extracted in the acid of formula V.
Then, formula V compound and the corresponding solution of amine in tetrahydrofuran (THF) are cooled to 0 ℃, add 1-hydroxyl-benzotriazole hydrate, diisopropyl ethyl amine and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night.Except that desolvating and handling, obtain the compound of required formula I by distillation in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.
Compound of the present invention has two three-dimensional centers.They can exist with the form of mixtures of epimerization form.A S-epimer always, another can be R, S or RS epimer.Can be separated into required epimerization form with known method own at the synthetic commitment, perhaps preferably during the late stages of developmet by the diastereo-isomerism product being separated the required epimerization form that is separated into chromatography.
With hereinafter given test described compound is studied.
The description of gamma-secretase test
In measuring of the test of gamma-secretase activity, the activity of test compound is assessed the proteolytic cleavage of suitable substrate.These tests can be test cell lines, wherein for example the substrate of gamma-secretase are merged in its kytoplasm zone, obtain a kind of transcription factor.With this fusion gene of cell transfecting and reporter gene firefly luciferase for example, described transcription factor increases its expression.Gamma-secretase will cause the expression of reporter gene to the cracking of merging substrate, can monitor it with suitable test.Can also measure the gamma-secretase activity with acellular in vitro tests, in this test, the cell lysate that for example will contain the gamma-secretase mixture is hatched with suitable APP-derived substrates (it is cracked into the Abeta peptide).The amount of the peptide that can be produced with the specific ELISA test determination.The clone secretion Abeta peptide in neurone source can be measured it with the specific ELISA test.Handle with the compound that suppresses gamma-secretase, cause secreted Abeta to reduce, thereby measure for restraining effect provides a kind of.
The active in vitro tests of gamma-secretase is used as the HEK293 membrane portions in gamma-secretase source and reorganization APP substrate.The latter by with the 6xHistidin afterbody (for purifying, its regulatable expression carrier for example among the pEt15 at expression in escherichia coli) 100 amino acid of the C-end of the people APP that merges form.This recombinant protein is with corresponding by the APP fragment of brachymemma, and this fragment produces after the gamma-secretase cracking in zone, extracellular and constitutes the gamma-secretase substrate.People such as Li YM, PNAS 97 (11), and 6138-6143 (2000) is described test principle.With Hek293 cell Mechanical Crushing, microsomal fraction is separated by differential centrifugation.Film is dissolved in washing composition (0.25%CHAPSO) and hatch with the APP substrate.With described (people such as Brockhaus M, Neuroreport 9 (7), the Abeta peptide that the ELISA test of 1481-1486 (1998) is produced the gamma-secretase cracking by this substrate detects.
Preferred compound shows＜IC of 700 (nM)
50The inhibiting data of gamma-secretase have been described in the tabulation below:
| Embodiment number | External IC 50(nM) | Embodiment number | External IC 50(nM) |
| 1a(R/S) | 4 | 7a(R/S) | 6 |
| 1b(R) | 2 | 7b(R) | 4 |
| 1c(S) | 3 | 7c(S) | 5 |
| 2a(R/S) | 10 | 8d(R/S) | 15 |
| 2b(R) | 38 | 9(R/S) | 630 |
| 2c(S) | 5 | 10(R/S) | 41 |
| 3a(R) | 260 | 11a(R/S) | 136 |
| 3b(S) | 11 | 11b(R) | 13 |
| 4a(R/S) | 89 | 12a(R/S) | 11 |
| 4b(S) | 8 | 12b(R) | 3.5 |
| 5c(R/S) | 110 | 13a(R) | 480 |
| 6a(R/S) | 15 | 13b(S) | 5 |
| 6g (R or S) | 118 | 14(R/S) | 30 |
| 6h (S or R) | 50 |
In addition, the thermodynamic solubility of also in the THESA test, having tested compound of the present invention.
The THESA test:
With every kind of compound of about 2mg excessive joining in the 50mM phosphate buffered saline buffer under room temperature (22.5 ± 1 ℃).Each sample is placed in the trace analysis pipe, with its ultrasonic 1h and stir 2h.All suspensions placements are spent the night.Second day, the pH with pH meter measurement all samples filtered sample so that solid matter and solution are separated with Micronic filter plate (MSGVN2250).With HPLC all solution are analyzed then.Compound with the different concns that is arranged in DMSO is set up lubber-line.Determine the solubleness of compound by this regression equation.
From following table as can be seen, compare with the compound of WO2005/023772, compound of the present invention has better solubleness or activity.
The compound useful as drug of formula I, for example the form with pharmaceutical preparation is used as medicine.Described pharmaceutical preparation can be by Orally administered, and is for example Orally administered with tablet, coated tablet, dragee (dragee), form hard and Gelseal, solution, emulsion or suspensoid.But also can rectum the form of suppository (for example with), the parenteral form of injection solution (for example with) use.
Can use the inorganic or organic carrier of the pharmaceutically inert that is used for useful in preparing drug formulations that formula I compound is processed.Lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc. can be as for example this class carriers of tablet, coated tablet, dragee and hard-gelatin capsules.The appropriate carrier that is used for Gelseal for example has vegetables oil, wax, fat, semisolid and liquid polyol etc.Yet,, under the situation of Gelseal, do not need carrier usually according to the character of active substance.The appropriate carrier that is used to prepare solution and syrup for example has water, polyvalent alcohol, glycerine, plant wet goods.The appropriate carrier that is used for suppository for example has natural or winterized stearin, wax, fat, semiliquid or liquid polyol etc.
In addition, pharmaceutical preparation can contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, correctives, the salt that is used to change osmotic pressure, buffer reagent, screening agent or antioxidant.They also can contain the material that other has therapeutic value.
Containing formula I compound or pharmaceutically acceptable salt thereof and treating the medicament of going up the inert carrier also is theme of the present invention, its preparation method is theme of the present invention equally, described preparation method comprise with one or more formulas I compound and/or pharmaceutically useful acid salt and if necessary one or more other have the material of therapeutic value to go up the inert carrier to make the galenic administration form with one or more treatments.
According to the present invention, the compound of formula I can be used for controlling or prevents disease based on the gamma-secretase inhibition, as alzheimer's disease or cancer.
Dosage can change in wide region, and will adapt with the individual demand in each particular case certainly.Under Orally administered situation, the dosage that is used to be grown up can be every day about 0.01mg to the compound of about 1000mg general formula I or its pharmaceutically useful salt of respective amount.This per daily dose can be used with single dose form or with the form of a plurality of divided doses, in addition, when suitable, also can surpass the described upper limit.
Tablet (wet granulation)
Preparation manipulation
1. project 1,2,3 and 4 is mixed, granulate with purified water.
2. at 50 ℃ of following dried particles.
3. make the grinding plant of particle by suiting.
4. adding project 5 was also mixed 3 minutes; On suitable tabletting machine, suppress.
Capsule
Preparation manipulation
1. project 1,2 and 3 was mixed 30 minutes in suitable mixing tank.
2. adding project 4 and 5 and mixed 3 minutes.
3. be filled in the suitable capsule.
Embodiment 1
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
With 101mg (0.45mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 119mg (0.45mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-five fluoro-propyl group)-solution of malonamic acid in the 15ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 61.8mg (0.45mmol) 1-hydroxyl-benzotriazole hydrate, 157 μ l (0.90mmol) diisopropyl ethyl amines and 87.6mg (0.45mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night.Mixture is poured into ice/waterborne and adds the 1N aqueous hydrochloric acid until its pH=1.Use extracted with diethyl ether,, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel with saturated sodium bicarbonate aqueous solution and salt water washing, with ethyl acetate/hexanaphthene 1/1 wash-out, obtain 86.1mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, be white solid, MS (m/e): 472.1 (M+H)
+
B) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
The base)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
C) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
Preparation HPLC by using YMC Pack SIL is to epimeric (the R/S)-2-of 124mg (0.27mmol) hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-the Malonamide mixture separates, with heptane/ethanol/Virahol/acetonitrile mixture wash-out, obtain 11mg (R or S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, epimer A (first is eluted), MS (m/e): 469.9 (M-H)
-, and 19mg (S or R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, epimer B (second is eluted), MS (m/e): 472.1 (M+H)
+
Embodiment 2
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(3,3,3-three fluoro-propyl group)-Malonamide
With 210mg (0.94mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 215mg (0.94mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-three fluoro-propyl group)-solution of malonamic acid in the 50ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 129mg (0.94mmol) 1-hydroxyl-benzotriazole hydrate, 327 μ l (1.87mmol) diisopropyl ethyl amines and 183mg (0.94mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night.Mixture is poured into ice/waterborne, adds the 1N aqueous hydrochloric acid until its pH=1.At first use extracted with diethyl ether, use ethyl acetate extraction then, with saturated sodium bicarbonate aqueous solution and salt water washing, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with ethyl acetate/heptane 2/1 wash-out, obtain 150mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(3,3,3-three fluoro-propyl group)-Malonamide, be white solid, MS (m/e): 436.1 (M+H)
+
B) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
The base)-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
C) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(3,3,3-three fluoro-propyl group)-Malonamide
Preparation HPLC by using Chiralpak AD is to epimeric (the R/S)-2-of 150mg (mmol) hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide mixture separates, and with ethanol/heptane 20/80 wash-out, obtains 60mg (R or S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(3,3,3-three fluoro-propyl group)-Malonamide, epimer A (first is eluted), MS (m/e): 436.1 (M+H)
+, and 75mg (S or R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(3,3,3-three fluoro-propyl group)-Malonamide, epimer B (second is eluted), MS (m/e): 436.1 (M+H)
+
Embodiment 3
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
A) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
With 70.0mg (0.31mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 73.9mg (0.34mmol) (R)-2-hydroxy-2-methyl-N-(2,2,2-three fluoro-ethyls)-solution of malonamic acid in the 6ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 46.4mg (0.34mmol) 1-hydroxyl-benzotriazole hydrate, 117 μ l (0.69mmol) diisopropyl ethyl amines and 65.8mg (0.34mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir 16 hours.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 100/0 to 25/75), obtain 101mg (77%) (R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,2-three fluoro-ethyls)-Malonamide, MS (m/e): 422.0 (M+H)
+
B) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
With 70.0mg (0.31mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 73.9mg (0.34mmol) (S)-2-hydroxy-2-methyl-N-(2,2,2-three fluoro-ethyls)-solution of malonamic acid in the 6ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 46.4mg (0.34mmol) 1-hydroxyl-benzotriazole hydrate, 117 μ l (0.69mmol) diisopropyl ethyl amines and 65.8mg (0.34mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir 16 hours.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 100/0 to 25/75), obtain 104mg (79%) (S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,2-three fluoro-ethyls)-Malonamide, MS (m/e): 422.0 (M+H)
+
Embodiment 4
(R/S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
(R)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
(S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
A) (R/S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
With 250mg (1.12mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 256mg (1.12mmol) (RS)-2-hydroxyl-2-(2; 2; 2-three fluoro-ethylamino formyl radicals)-solution of butyric acid in the 24ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 174mg (0.94mmol) 1-hydroxyl-benzotriazole hydrate, 390 μ l (2.23mmol) diisopropyl ethyl amines and 218mg (1.12mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with ethyl acetate/heptane 2/8 wash-out, obtain 330mg (68%) (R/S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,2-three fluoro-ethyls)-Malonamide, be colorless oil, MS (m/e): 436.1 (M+H)
+
B) (R)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
The base)-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
C) (S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N '-(2,2,2-three fluoro-ethyls)-Malonamide
Preparation HPLC by using Chiralpak AD is to epimeric (the R/S)-2-ethyl of 310mg (mmol)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide mixture separates, and with Virahol/heptane 15/85 wash-out, obtains 120mg (R or S)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,2-three fluoro-ethyls)-Malonamide, epimer A (first is eluted), MS (m/e): 436.1 (M+H)
+, and 120mg (S or R)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N '-(2,2,2-three fluoro-ethyls)-Malonamide, epimer B (second is eluted), MS (m/e): 436.1 (M+H)
+
Embodiment 5
(R/S)-N-cyclopropyl methyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-Malonamide
A) (R/S)-2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
The amino first of-7-base
Acyl group)-Valeric acid ethylester
With 500mg (2mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 466mg (2mmol) (RS)-the 2-hydroxyl-solution of 2-propyl group-monoethyl malonate in the 40ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 331mg (2mmol) 1-hydroxyl-benzotriazole hydrate, 830 μ l (5mmol) diisopropyl ethyl amines and 470mg (2mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 90/10 to 50/50), obtain 630mg (71%) (R/S)-2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-and Valeric acid ethylester, be colourless foam, MS (m/e): 397.3 (M+H)
+
B) (R/S)-2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
The amino first of-7-base
Acyl group)-valeric acid
600mg (2mmol) is arranged in (R/S)-2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, the d] azepine of 8ml tetrahydrofuran (THF)
-7-base formamyl)-mixture that Valeric acid ethylester and 70.0mg (2mmol) are arranged in the lithium hydroxide of 4ml water at room temperature stirs and spends the night.Solvent evaporated, with ethyl acetate in 1 time extracted residues of pH, obtain 450mg (81%) (R/S)-2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-and valeric acid, MS (m/e): 367.1 (M-H)
-
C) (R/S)-N-cyclopropyl methyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-Malonamide
With 70.0mg (0.19mmol) 2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and the solution of 14.9mg (0.21mmol) cyclopropane methylamine in the 3ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 28.2mg (0.21mmol) 1-hydroxyl-benzotriazole hydrate, 71 μ l (0.42mmol) diisopropyl ethyl amines and 40.1mg (0.21mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night.Desolvate by distilling to remove, handle in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with heptane/eluent ethyl acetate (gradient 90: 10 to 50: 50), obtain 50.0mg (62%) (R/S)-N-cyclopropyl methyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-Malonamide: MS (m/e): 422.4 (M+H)
+
Embodiment 6
(R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide
(R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide and
(S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-the 2-propyl group
-N-(3,3,3-three fluoro-propyl group)-Malonamide
With 70.0mg (0.19mmol) 2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and 31.3mg (0.21mmol) 3; 3; the solution of 3-trifluoro propyl amine hydrochlorate in the 3ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 28.2mg (0.21mmol) 1-hydroxyl-benzotriazole hydrate, 103 μ l (0.61mmol) diisopropyl ethyl amines and 40.1mg (0.21mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 90: 10 to 50: 50), obtain 50.0mg (57%) (R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide: MS (m/e): 464.0 (M+H)
+
B) 2-hydroxyl-2-propyl group-monoethyl malonate
At room temperature, use air bubbling 1 hour in the suspension in the 120ml dimethyl formamide to 15.0g (72.7mmol) propanedioic acid diethyl propyl diester and 47.6g (145mmol) cesium carbonate.Under 10-20 ℃, add 150ml water and at room temperature continue and stirred 3 hours.Remove most of dimethyl formamide by vacuum distilling under 35 ℃ of bath temperature then.Add 1l water and use extracted with diethyl ether, obtain 11.7g 2-hydroxyl-2-propyl group-monoethyl malonate, MS (m/e): 189.1 (M-H)
-
C) 2-hydroxyl-2-(3,3,3-trifluoro propyl formamyl) Valeric acid ethylester
To measure for 4.03g (～21mmol) 2-hydroxyl-2-propyl group-monoethyl malonate is dissolved in the 200ml tetrahydrofuran (THF) and is cooled to 0 ℃.Add 2.92g (21.2mmol) 1-hydroxyl-benzotriazole hydrate, 12.9ml (74.1mmol) diisopropyl ethyl amine and 4.14g (21.2mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride, at room temperature continue to stir 4 days.Add 45ml 2N aqueous hydrochloric acid.Use ethyl acetate extraction, use the salt water washing, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel; with ethyl acetate/hexanaphthene 3/1 wash-out, obtain 4.60g (76%) 2-hydroxyl-2-(3,3; 3-trifluoro propyl formamyl) Valeric acid ethylester is yellow oil, MS (m/e): 286.1 (M+H)
+
D) (R and S)-2-hydroxyl-2-(3,3,3-trifluoro propyl formamyl) Valeric acid ethylester
Chromatography by using Chiralpak AD is with racemic 2-hydroxyl-2-(3; 3; 3-trifluoro propyl formamyl) Valeric acid ethylester is separated into enantiomorph; with Virahol/heptane 10/90 wash-out; obtain 0.96g (21%) (R or S)-2-hydroxyl-2-(3; 3,3 trifluoro propyl formamyls) Valeric acid ethylester (enantiomorph that first is eluted), MS (m/e): 286.1 (M+H)
+, and 1.09g (24%) (S or R)-2-hydroxyl-2-(3,3,3-trifluoro propyl formamyl) Valeric acid ethylesters (second enantiomorph that quilt elutes), MS (m/e): 286.4 (M+H)
+
E) (R or S)-2-hydroxyl-2-(3,3,3-three fluoro-propyl group formamyls)-valeric acid, entity A
With solution and 880mg (3.09mmol) (R or the S)-2-hydroxyl-2-(3 that be arranged in 18ml tetrahydrofuran (THF) of 131mg (3.09mmol) lithium hydroxide in 8ml water; 3,3 trifluoro propyl formamyls) Valeric acid ethylester (first enantiomorph that is eluted of back) at room temperature stirs together and spends the night.At first water/extracted with diethyl ether is used 1N aqueous hydrochloric acid/ethyl acetate extraction then, obtains 744mg (93%) (R or S)-2-hydroxyl-2-(3,3,3-three fluoro-propyl group formamyls)-valeric acid, entity A, MS (m/e): 256.1 (M-H)
-
F) (S or R)-2-hydroxyl-2-(3,3,3-three fluoro-propyl group formamyls)-valeric acid, entity B
With solution and 1.06g (3.72mmol) (S or the R)-2-hydroxyl-2-(3 of 158mg (3.72mmol) lithium hydroxide in 8.5ml water; 3,3 trifluoro propyl formamyls) Valeric acid ethylester (enantiomorph that second quilt of step c) elutes) at room temperature stirs together and spends the night.At first water/extracted with diethyl ether is used 1N aqueous hydrochloric acid/ethyl acetate extraction then, obtains 870mg (91%) (S or R)-2-hydroxyl-2-(3,3,3-three fluoro-propyl group formamyls)-valeric acid, entity B, MS (m/e): 256.1 (M-H)
-
G) (R or S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-third
Base-N-(3,3,3-three fluoro-propyl group)-Malonamide, entity A
With 135mg (0.60mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 154mg (0.60mmol) (R or S)-2-hydroxyl-2-(3; 3; 3-three fluoro-propyl group formamyls)-valeric acid; the solution of entity A in the 10ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 93.8mg (0.60mmol) 1-hydroxyl-benzotriazole hydrate, 210 μ l (1.20mmol) diisopropyl ethyl amines and 117mg (0.60mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night., handle except that desolvating by distillation,, obtain 218mg (78%) (R or S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine with ethyl acetate/heptane wash-out (gradient 10: 90 to 100: 0) in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel
-7-yl)-and 2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide, entity A: MS (m/e): 462.0 (M-H)
-
H) (S or R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-
Propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide, entity B
With 135mg (0.60mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 154mg (0.60mmol) (S or R)-2-hydroxyl-2-(3; 3; 3-three fluoro-propyl group formamyls)-valeric acid; the solution of entity B in the 10ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 93.8mg (0.60mmol) 1-hydroxyl-benzotriazole hydrate, 210 μ l (1.20mmol) diisopropyl ethyl amines and 117mg (0.60mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night., handle except that desolvating by distillation,, obtain 221mg (80%) (S or R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine with ethyl acetate/heptane wash-out (gradient 10: 90 to 100: 0) in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel
-7-yl)-and 2-propyl group-N-(3,3,3-three fluoro-propyl group)-Malonamide, entity B: MS (m/e): 462.0 (M-H)
-
Embodiment 7
(R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide
(R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide and
(S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide
A) (R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide
With 70.0mg (0.19mmol) 2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and 31.2mg (0.21mmol) 2; 2; 3; 3; the solution of 3-five fluoropropyl amine in the 3ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 28.2mg (0.21mmol) 1-hydroxyl-benzotriazole hydrate, 72 μ l (0.42mmol) diisopropyl ethyl amines and 40.1mg (0.21mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 90: 10 to 50: 50), obtain 60.0mg (63%) (R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide: MS (m/e): 500.4 (M+H)
+
B) (R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
The base)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide and
C) (S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide
Preparation HPLC by using Chiralpak AD is to epimeric (the R/S)-2-of 500mg (1.0mmol) hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide mixture separates, and with 90: 10 wash-outs of heptane/ethanol, obtains 115mg (22%) (R or S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide, epimer A (first is eluted), MS (m/e): 500.4 (M+H)
+, and 95mg (19%) (S or R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide, epimer B (second is eluted), MS (m/e): 500.4 (M+H)
+
Embodiment 8
(R/S)-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxyl-2-isobutyl--propanedioic acid mono-methyl
At room temperature, use air bubbling 1 hour in the suspension in the 7ml dimethyl formamide to 0.5g (3mmol) (2-methyl-propyl) dimethyl malonate and 1.73g (5mmol) cesium carbonate.At room temperature continue to stir 24 hours.Add 25ml water, use the extracted with diethyl ether mixture.Be acidified to pH=1 and use ethyl acetate extraction with the 1N aqueous hydrochloric acid, obtain 0.42g (83%) (R/S)-2-hydroxyl-2-isobutyl--propanedioic acid mono-methyl, MS (m/e): 189.4 (M-H)
-
B) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base
Formamyl)-methyl valerate
With 350mg (1.56mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 327mg (1.72mmol) (R/S)-the 2-hydroxyl-2-isobutyl--solution of propanedioic acid mono-methyl in the 30ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 232mg (1.72mmol) 1-hydroxyl-benzotriazole hydrate, 584 μ l (3.43mmol) diisopropyl ethyl amines and 329mg (192mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night.Water/ethyl acetate extraction is handled in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with heptane/eluent ethyl acetate (gradient 90/10 to 50/50), obtain 470mg (76%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-and methyl valerate, be colourless foam, MS (m/e): 397.3 (M+H)
+
C) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base
Formamyl)-valeric acid
430mg (1.09mmol) is arranged in (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, the d] azepine of 6ml tetrahydrofuran (THF)
-7-base formamyl)-mixture that methyl valerate and 50.1mg (1.19mmol) are arranged in the lithium hydroxide monohydrate of 3ml at room temperature stirs and spends the night.Solvent evaporated extracts resistates with ethyl acetate for 1 time at pH, obtain 390mg (94%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-and valeric acid, MS (m/e): 381.0 (M-H)
-
D) (R/S)-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-
Base)-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
With 50.0mg (0.13mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and 39.0mg (0.26mmol) 2; 2; 3; 3; the solution of 3-five fluoropropyl amine in the 1.5ml dimethyl formamide is cooled to 0 ℃, adds 20 μ l (0.14mmol) triethylamines and 54.5mg (0.14mmol) phosphofluoric acid O-(benzotriazole-1-yl)-N, N; N ', N '-tetramethyl-urea (HBTU).Continue to stir and spend the night.Remove by distillation and to desolvate, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, with heptane/eluent ethyl acetate (gradient 19: 1 to 1: 1), obtain 45.0mg (67%) (R/S)-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide: MS (m/e): 514.5 (M+H)
+
Embodiment 9
(R/S)-N-cyclopropyl methyl-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-Malonamide
With 50.0mg (0.13mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and the solution of 18.6mg (0.26mmol) cyclopropane methylamine in the 1.5ml dimethyl formamide is cooled to 0 ℃; add 20 μ l (0.14mmol) triethylamines and 54.5mg (0.14mmol) phosphofluoric acid O-(benzotriazole-1-yl)-N; N; N ', N '-tetramethyl-urea is failed (HBTU).At room temperature continue to stir weekend.Desolvate by distilling to remove, handle in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, with heptane/eluent ethyl acetate (gradient 19: 1 to 1: 1), obtain 10.0mg (18%) (R/S)-N-cyclopropyl methyl-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and Malonamide, MS (m/e): 436.1 (M+H)
+
Embodiment 10
(R/S)-N-(3,5-two fluoro-benzyls)-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-Malonamide
With 50.0mg (0.13mmol) 2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and 37.4mg (0.26mmol) 3; the solution of 5-difluorobenzyl amine in the 1.5ml dimethyl formamide is cooled to 0 ℃; add 20 μ l (0.14mmol) triethylamines and 54.5mg (0.14mmol) phosphofluoric acid O-(benzotriazole-1-yl)-N; N; N ', N '-tetramethyl-urea (HBTU).At room temperature continue to stir to spend the night., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with heptane/eluent ethyl acetate (gradient 19: 1 to 1: 1), obtain 10.0mg (15%) (R/S)-N-(3,5-two fluoro-benzyls)-2-hydroxyl-2-isobutyl--N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-and Malonamide, MS (m/e): 508.5 (M+H)
+
Embodiment 11
(R/S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
(R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
(S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide
With 200mg (0.65mmol) (S)-7-amino-5-(2,2,2-three fluoro-ethyls)-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 150mg (0.65mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-three fluoro-propyl group)-solution of malonamic acid in the 7ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 102mg (0.65mmol) 1-hydroxyl-benzotriazole hydrate, 228 μ l (1.31mmol) diisopropyl ethyl amines and 128mg (0.65mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.At room temperature continue to stir to spend the night., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with ethyl acetate/heptane wash-out (gradient 1/4 to 4/1), obtain 220mg (65%) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide, be white solid, MS (m/e): 518.2 (M+H)
+
B) (R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide and
C) (S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo
[b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide,
Preparation HPLC by using Chiralpak AD is to epimeric (the R/S)-2-of 200mg hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide mixture separates, with Virahol/heptane 15/85 wash-out, obtain 90mg (R or S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide, epimer A (first is eluted), MS (m/e): 518.5 (M+H)
+, and 90mg (S or R)-2-hydroxy-2-methyl-N-[(S)-and 6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(3,3,3-three fluoro-propyl group)-Malonamide, epimer B (second is eluted), MS (m/e): 518.5 (M+H)
+
Embodiment 12
(R/S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
(R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
(S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
A) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
Make 144mg (0.47mmol) (S)-7-amino-5-(2,2,2-three fluoro-ethyls)-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 125mg (0.47mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-five fluoro-propyl group)-solution of malonamic acid in the 21ml tetrahydrofuran (THF) at room temperature with 73.6mg (0.47mmol) 1-hydroxyl-benzotriazole hydrate, 165 μ l (0.94mmol) diisopropyl ethyl amines and 92.1mg (0.47mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride reaction.Continue to stir and spend the night., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with ethyl acetate/heptane wash-out (gradient 15/85 to 40/60), obtain 207mg (79%) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, be white solid, MS (m/e): 554.3 (M+H)
+
B) (R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide and
C) (S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo
[b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide
Preparation HPLC by using Chiralcel OD is to epimeric (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-the Malonamide mixture separates, and with Virahol/heptane 10/90 wash-out, obtains 40mg (R or S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, epimer A (first is eluted), MS (m/e): 554.3 (M+H)
+, and 40mg (S or R)-2-hydroxy-2-methyl-N-[(S)-and 6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, epimer B (second is eluted), MS (m/e): 554.3 (M+H)
+
Embodiment 13
(R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
(S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide
A) (R)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide and
With 75.0mg (0.25mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 52.7mg (0.25mmol) (R)-2-hydroxy-2-methyl-N-(2,2,2-three fluoro-ethyls)-solution of malonamic acid in the 7ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 33.8mg (0.25mmol) 1-hydroxyl-benzotriazole hydrate, 86 μ l (0.49mmol) diisopropyl ethyl amines and 47.9mg (0.25mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir 16 hours., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with heptane/eluent ethyl acetate (gradient 10/90 to 40/60), obtain 37mg (30%) (R)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide, MS (m/e): 504.4 (M+H)
+
B) (S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-hexichol
And [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide
With 75.0mg (0.25mmol) (S)-7-amino-5H, 7H-dibenzo [b, d] azepine
-6-ketone and 52.7mg (0.25mmol) (S)-2-hydroxy-2-methyl-N-(2,2,2-three fluoro-ethyls)-solution of malonamic acid in the 7ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 33.8mg (0.25mmol) 1-hydroxyl-benzotriazole hydrate, 86 μ l (0.49mmol) diisopropyl ethyl amines and 47.9mg (0.25mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with heptane/eluent ethyl acetate (gradient 10/90 to 40/60), obtain 38mg (31%) (S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide, MS (m/e): 504.4 (M+H)
+
Embodiment 14
(R/S)-N-(2,2-two fluoro-propyl group)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] nitrogen
Assorted
-7-yl)-2-propyl group-Malonamide
With 50.0mg (0.14mmol) 2-hydroxyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-base formamyl)-valeric acid and 14.2mg (0.15mmol) 2; the solution of 2-two fluoropropyl amine in the 2.5ml tetrahydrofuran (THF) is cooled to 0 ℃, adds 20.2mg (0.15mmol) 1-hydroxyl-benzotriazole hydrate, 39 μ l (0.3mmol) diisopropyl ethyl amines and 28.6mg (0.15mmol) N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride.Continue to stir and spend the night., handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, except that desolvating by distillation with heptane/eluent ethyl acetate (gradient 90: 10 to 50: 50), obtain 30.0mg (50%) (R/S)-N-(2,2-two fluoro-propyl group)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-2-propyl group-Malonamide: MS (m/e): 446.1 (M+H)
+
Claims (11)
1. the 6-oxo-6 of formula I, 7-dihydro-5H-dibenzo [b, d] azepine
-7-radical derivative,
Wherein
R
1Be hydrogen or the low alkyl group that replaced by halogen;
R
2It is low alkyl group;
R
3The low alkyl group that is replaced by halogen ,-(CH
2)
n-cycloalkyl or-(CH
2)
n-phenyl, wherein benzyl ring is unsubstituted or is replaced by halogen;
N is 0,1 or 2;
Or its suitable medicinal optically pure epimer or mixture.
2. formula I compound according to claim 1, wherein R
1Be hydrogen and R
3The low alkyl group that is replaced by halogen.
3. formula I compound according to claim 2, this compound is
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,3,3,3-five fluoro-propyl group)-Malonamide,
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(3,3,3-three fluoro-propyl group)-Malonamide,
(R)-2-ethyl-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N '-(2,2,2-three fluoro-ethyls)-Malonamide,
(R/S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide,
(R)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide, or
(S)-2-hydroxy-n-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl)-N-(2,2,3,3,3-five fluoro-propyl group)-2-propyl group-Malonamide.
4. formula I compound according to claim 1, wherein R
1The low alkyl group and the R that are replaced by halogen
3The low alkyl group that is replaced by halogen.
5. formula I compound according to claim 4, this compound is
(R)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N-(2,2,3,3,3-five fluoro-propyl group)-Malonamide, or
(S)-the 2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-three fluoro-ethyls)-6,7-dihydro-5H-dibenzo [b, d] azepine
-7-yl]-N '-(2,2,2-three fluoro-ethyls)-Malonamide.
6. the method for preparing defined formula I compound among the claim 1-5, this method comprises
A) with the compound of formula II
With the compound reaction of formula III,
Obtain the compound of formula I,
Substituting group wherein has the implication described in the claim 1, perhaps,
B) with the compound of formula IV
With formula NH
2R
3Amine reaction, obtain the compound of formula I,
Substituting group wherein has the implication described in the claim 1,
With,
If necessary, the mixture (R/S) with the epimerization form of formula I compound changes into epimer (R) and epimer (S).
7. according to any described compound among the claim 1-5, it is to prepare with method described in the claim 6 or the method suitable with it.
8. medicament, it comprises any described compound and pharmaceutically useful vehicle among one or more claims 1-5.
9. medicament according to claim 8, it is used for the treatment of alzheimer's disease or cancer.
10. any one compound is used for the treatment of purposes in the medicament of alzheimer's disease or cancer in preparation among the claim 1-5.
11. invention mentioned above.
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| CN102911118A (en) * | 2012-11-09 | 2013-02-06 | 天津商业大学 | Benzo-azepine type derivative and preparation method and purpose thereof |
| CN104854094A (en) * | 2012-09-21 | 2015-08-19 | 百时美施贵宝公司 | Fluoroalkyl dibenzodiazepinone compounds |
| CN109320456A (en) * | 2018-11-16 | 2019-02-12 | 天津商业大学 | Antitumoral compounds of novel crystal forms and preparation method thereof and composition containing it |
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| EP2897954B1 (en) | 2012-09-21 | 2016-10-26 | Bristol-Myers Squibb Company | Fluoroalkyl-1,4-benzodiazepinone compounds |
| WO2014047374A1 (en) | 2012-09-21 | 2014-03-27 | Bristol-Myers Squibb Company | Alkyl, fluoroalkyl-1,4-benzodiazepinone compounds |
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| WO2015073524A1 (en) * | 2013-11-12 | 2015-05-21 | Drexel University | Novel methods of treating or preventing alzheimer's disease |
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| WO2001077086A1 (en) | 2000-04-11 | 2001-10-18 | Dupont Pharmaceuticals Company | SUBSTITUTED LACTAMS AS INHIBITORS OF Aβ PROTEIN PRODUCTION |
| GB0012671D0 (en) | 2000-05-24 | 2000-07-19 | Merck Sharp & Dohme | Therapeutic agents |
| CN100480248C (en) * | 2003-02-04 | 2009-04-22 | 弗·哈夫曼-拉罗切有限公司 | Malonamide derivatives as gamma-secretase inhibitors |
| KR20070087233A (en) * | 2003-09-09 | 2007-08-27 | 에프. 호프만-라 로슈 아게 | Malonamide derivatives blocking the activity of gama-secretase |
| DK1673347T3 (en) | 2003-10-06 | 2015-10-12 | Hoffmann La Roche | SUBSTITUTED DIBENZO-AZEPINE AND BENZO-DIAZEPINE DERIVATIVES USED AS GAMMA SECRETASE INHIBITORS |
| US7211573B2 (en) * | 2004-12-08 | 2007-05-01 | Hoffmann-La Roche Inc. | Malonamide derivatives |
| CN101410378B (en) * | 2006-03-27 | 2012-12-05 | 霍夫曼-拉罗奇有限公司 | Malonamide derivatives as gamma secretase inhibitors |
| BRPI0717587A2 (en) * | 2006-09-20 | 2013-10-29 | Hoffmann La Roche | 4-OXO-2,3,4,5-TETRA-HYDRO-BENZO DERIVATIVES [B] [1,4] DIAZEPINE |
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2008
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- 2008-01-23 CN CN200880006496A patent/CN101622232A/en active Pending
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- 2008-01-23 BR BRPI0807341-4A patent/BRPI0807341A2/en not_active IP Right Cessation
- 2008-01-23 EP EP08701648A patent/EP2109604A1/en not_active Ceased
- 2008-01-23 AU AU2008209861A patent/AU2008209861B2/en not_active Expired - Fee Related
- 2008-01-23 CA CA002676160A patent/CA2676160A1/en not_active Abandoned
- 2008-01-23 WO PCT/EP2008/050768 patent/WO2008092786A1/en active Application Filing
- 2008-01-23 JP JP2009547643A patent/JP2010517954A/en active Pending
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- 2008-01-30 CL CL200800254A patent/CL2008000254A1/en unknown
- 2008-01-30 PE PE2008000215A patent/PE20081662A1/en not_active Application Discontinuation
- 2008-01-30 TW TW097103532A patent/TW200846005A/en unknown
- 2008-02-01 AR ARP080100419A patent/AR065129A1/en unknown
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102893155A (en) * | 2010-05-19 | 2013-01-23 | 霍夫曼-拉罗奇有限公司 | Combination therapy and method for assessing resistance to treatment |
| CN102893155B (en) * | 2010-05-19 | 2016-01-20 | 霍夫曼-拉罗奇有限公司 | Conjoint therapy and the method for assessment of the resistance to treatment |
| CN104854094A (en) * | 2012-09-21 | 2015-08-19 | 百时美施贵宝公司 | Fluoroalkyl dibenzodiazepinone compounds |
| CN102911118A (en) * | 2012-11-09 | 2013-02-06 | 天津商业大学 | Benzo-azepine type derivative and preparation method and purpose thereof |
| CN102911118B (en) * | 2012-11-09 | 2014-04-09 | 天津商业大学 | Benzo-azepine type derivative and preparation method and purpose thereof |
| CN109320456A (en) * | 2018-11-16 | 2019-02-12 | 天津商业大学 | Antitumoral compounds of novel crystal forms and preparation method thereof and composition containing it |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200846005A (en) | 2008-12-01 |
| AR065129A1 (en) | 2009-05-20 |
| AU2008209861A1 (en) | 2008-08-07 |
| US7544679B2 (en) | 2009-06-09 |
| MX2009007864A (en) | 2009-07-31 |
| PE20081662A1 (en) | 2008-11-22 |
| IL199973A0 (en) | 2010-04-15 |
| KR20090104916A (en) | 2009-10-06 |
| US20080188463A1 (en) | 2008-08-07 |
| CA2676160A1 (en) | 2008-08-07 |
| BRPI0807341A2 (en) | 2014-05-20 |
| KR101150574B1 (en) | 2012-05-30 |
| JP2010517954A (en) | 2010-05-27 |
| EP2109604A1 (en) | 2009-10-21 |
| AU2008209861B2 (en) | 2012-08-09 |
| WO2008092786A1 (en) | 2008-08-07 |
| CL2008000254A1 (en) | 2008-08-08 |
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